Biotechnology and Biological Sciences Research Council (BBSRC)
BB/T01508X/1
European Union
European Research Council (ERC)
647278
European Union
Citation
Journal: Mol Cell / Year: 2021 Title: Structure, mechanism, and inhibition of Hedgehog acyltransferase. Authors: Claire E Coupland / Sebastian A Andrei / T Bertie Ansell / Loic Carrique / Pramod Kumar / Lea Sefer / Rebekka A Schwab / Eamon F X Byrne / Els Pardon / Jan Steyaert / Anthony I Magee / ...Authors: Claire E Coupland / Sebastian A Andrei / T Bertie Ansell / Loic Carrique / Pramod Kumar / Lea Sefer / Rebekka A Schwab / Eamon F X Byrne / Els Pardon / Jan Steyaert / Anthony I Magee / Thomas Lanyon-Hogg / Mark S P Sansom / Edward W Tate / Christian Siebold / Abstract: The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate ...The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.
Protein-cysteineN-palmitoyltransferaseHHAT / Hedgehog acyltransferase / Melanoma antigen recognized by T-cells 2 / MART-2 / Skinny hedgehog protein 1
Mass: 58327.754 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HHAT, MART2, SKI1 / Plasmid: pHR-CMV-TetO2 / Cell line (production host): HEK293S GnTI-/- / Production host: Homo sapiens (human) References: UniProt: Q5VTY9, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Antibody
Megabody177
Mass: 102601.586 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Escherichia coli K-12 (bacteria) / Plasmid: pMESP23E2 / Production host: Escherichia coli (E. coli) / Strain (production host): WK6
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